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• W2007991612 abstract "Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing. Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing. Diabetes mellitus and diabetic nephropathy (DN) are disorders that result, in part, from a dysregulation of the immune system. Proinflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6, and C-reactive protein in patients with DN suggest that chronic low-grade inflammation is a characteristic of DN.1.Parving H.H. Osterby R. Ritz E. Diabetic nephropathy.in: Brenner B.M. The Kidney. WB Saunders Company, Philadelphia2000: 1731-1773Google Scholar, 2.Cooper M.E. Pathogenesis, prevention, and treatment of diabetic nephropathy.Lancet. 1998; 352: 213-219Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 3.Nikolic-Paterson D.J. Atkins R.C. The role of macrophages in glomerulonephritis.Nephrol Dial Transplant. 2001; 16: 3-7Crossref PubMed Scopus (130) Google Scholar Activated T-lymphocytes have been associated with DN and correlated with initiation of early-stage proteinuria in type 1 and type 2 diabetes.4.Bending J.J. Lobo-Yeo A. Vergani D. et al.Proteinuria and activated T-lymphocytes in diabetic nephropathy.Diabetes. 1988; 37: 507-511Crossref PubMed Scopus (40) Google Scholar, 5.Moriya R. Manivel J.C. Mauer M. Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients.Diabetologia. 2004; 47: 82-88Crossref PubMed Scopus (44) Google Scholar Infiltration of CD4+ and CD8+ T cells, as well as overexpression of major histocompatibility complex class I and II molecules, on lymphocytes may have an important role in the pathogenesis of both immune-mediated and non-immune-mediated inflammatory kidney disease associated with DN.6.Mensah-Brown E.P. Obineche E.N. Galadari S. et al.Streptozotocin-induced diabetic nephropathy in rats: the role of inflammatory cytokines.Cytokine. 2005; 31: 180-190Crossref PubMed Scopus (65) Google Scholar These findings point to the role of chronic mild inflammation and T cells in the pathogenesis of DN. Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, is produced by phosphorylation of sphingosine by sphingosine kinases (SphKs; SphK1, and SphK2) in response to a variety of stimuli. S1P binds to five related G-protein-coupled receptors, termed S1P1–5Rs.7.Hla T. Lee M.J. Ancellin N. et al.Lysophospholipids—receptor revelations.Science. 2001; 294: 1875-1878Crossref PubMed Scopus (465) Google Scholar S1P receptors regulate a wide variety of important cellular functions, including cell survival, cytoskeletal rearrangements, and cell motility.7.Hla T. Lee M.J. Ancellin N. et al.Lysophospholipids—receptor revelations.Science. 2001; 294: 1875-1878Crossref PubMed Scopus (465) Google Scholar, 8.Rosen H. Goetzl E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.Nat Rev Immunol. 2005; 5: 560-570Crossref PubMed Scopus (595) Google Scholar We and others have shown that S1P1 receptors (S1P1Rs) are expressed in kidneys as well as on bone-marrow-derived cells, and on activation reduce inflammation.9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar, 10.Lien Y.H. Yong K.C. Cho C. et al.S1P(1)-selective agonist, SEW2871, ameliorates ischemic acute renal failure.Kidney Int. 2006; 69: 1601-1608Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar FTY720, a non-selective S1P1R agonist, and SEW2871, a selective S1P1R agonist, elicit lymphopenia resulting from reversible redistribution of lymphocytes from the circulation to secondary lymphatic tissue.11.Mandala S. Hajdu R. Bergstrom J. et al.Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.Science. 2002; 296: 346-349Crossref PubMed Scopus (1367) Google Scholar, 12.Pinschewer D.D. Ochsenbein A.F. Odermatt B. et al.FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.J Immunol. 2000; 164: 5761-5770Crossref PubMed Scopus (324) Google Scholar FTY720 is a pro-drug and is phosphorylated by SphK1 and SphK2 into its active form.13.Brinkmann V. Davis M.D. Heise C.E. et al.The immune modulator FTY720 targets sphingosine 1-phosphate receptors.J Biol Chem. 2002; 277: 21453-21457Crossref PubMed Scopus (1249) Google Scholar Notably, previous studies demonstrated a remarkable protective effect of FTY720 in models of multiple sclerosis,13.Brinkmann V. Davis M.D. Heise C.E. et al.The immune modulator FTY720 targets sphingosine 1-phosphate receptors.J Biol Chem. 2002; 277: 21453-21457Crossref PubMed Scopus (1249) Google Scholar, 14.Fujino M. Funeshima N. Kitazawa Y. et al.Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment.J Pharmacol Exp Ther. 2003; 305: 70-77Crossref PubMed Scopus (258) Google Scholar autoimmune myocarditis,15.Kitabayashi H. Isobe M. Watanabe N. et al.FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes.J Cardiovasc Pharmacol. 2000; 35: 410-416Crossref PubMed Scopus (62) Google Scholar uveoretinitis,16.Kurose S. Ikeda E. Tokiwa M. et al.Effects of FTY720, a novel immunosuppressant, on experimental autoimmune uveoretinitis in rats.Exp Eye Res. 2000; 70: 7-15Crossref PubMed Scopus (61) systemic lupus erythematosus,17.Okazaki H. Hirata D. Kamimura T. et al.Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus.J Rheumatol. 2002; 29: 707-716PubMed Google Scholar and atherosclerosis.18.Keul P. Tolle M. Lucke S. et al.The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice.Arterioscler Thromb Vasc Biol. 2007; 27: 607-613Crossref PubMed Scopus (133) Google Scholar FTY720 prevents autoimmune diabetes in non-obese diabetic mice by preventing the development of hyperglycemia and insulinitis.19.Maki T. Gottschalk R. Monaco A.P. Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice.Transplantation. 2002; 74: 1684-1686Crossref PubMed Scopus (46) Google Scholar, 20.Maki T. Gottschalk R. Ogawa N. et al.Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720.Transplantation. 2005; 79: 1051-1055Crossref PubMed Scopus (60) Google Scholar, 21.Yang Z. Chen M. Fialkow L.B. et al.The immune modulator FYT720 prevents autoimmune diabetes in nonobese diabetic mice small star, filled.Clin Immunol. 2003; 107: 30-35Crossref PubMed Scopus (57) Google Scholar However, these studies mainly focused on the effect of FTY720 on the pancreas. In humans, FTY720 has been shown to be efficacious in relapsing multiple sclerosis,22.Kappos L. Radue E.W. O'Connor P. et al.A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.N Engl J Med. 2010; 362: 387-401Crossref PubMed Scopus (1952) Google Scholarand has been recently approved by the Food and Drug Administration for the treatment of multiple sclerosis. We have demonstrated that activation of S1P1Rs protects the kidney by reducing inflammation, leukocyte infiltration, and vascular permeability associated with acute renal ischemia–reperfusion injury, primarily by peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1Rs.9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar, 23.Bajwa A. Jo S.K. Ye H. et al.Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury.J Am Soc Nephrol. 2010; 21: 955-965Crossref PubMed Scopus (84) Google Scholar Whether FTY720 or other S1P1R agonists have an effect to reduce inflammation, proteinuria, and histological changes associated with DN is not known. Because lymphocytes may contribute to early-stage proteinuria,4.Bending J.J. Lobo-Yeo A. Vergani D. et al.Proteinuria and activated T-lymphocytes in diabetic nephropathy.Diabetes. 1988; 37: 507-511Crossref PubMed Scopus (40) Google Scholar, 5.Moriya R. Manivel J.C. Mauer M. Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients.Diabetologia. 2004; 47: 82-88Crossref PubMed Scopus (44) Google Scholar we hypothesized that activation of S1P1Rs would ameliorate renal tissue injury associated with early-stage DN. Using streptozotocin (STZ)-induced rat and mouse animal models, we show that chronic S1P1R activation by FTY720 or SEW2871 prevents functional and structural changes induced by diabetes by ameliorating urinary albumin excretion (UAE), urinary TNF-α, podocyte-specific proteins, podocyte TNF-α and vascular endothelial growth factor (VEGF) mRNA expression, and tubule vesicular injury and vacuolization. The mechanism(s) by which FTY720 and SEW2871 reduce the functional and morphological changes induced by diabetes appear(s) to be independent of lymphocytes, and is likely mediated primarily by S1P1Rs and not by S1P3Rs. To our knowledge, this study provides for the first time evidence of the protective role of S1P1R agonists in DN and demonstrates that targeting kidney S1P1Rs may be a novel therapeutic intervention in the treatment of DN. Effects of FTY720 and SEW2871 on blood glucose, body weight, systolic blood pressure, and urinary volume in rats at 9 weeks were studied. Blood glucose levels increased significantly in the diabetes groups treated with vehicle, FTY720, or SEW2871 throughout the study period (Table 1). Control rats gained weight as expected. The increase in body weight in vehicle- and drug-treated diabetic groups was modest, and body weight in diabetic groups was markedly lower than control rats at week 9. There was a significant increase in urinary volume in diabetic groups. There were no significant changes in systolic blood pressure at 9 weeks after STZ induction of diabetes in any group.Table 1Changes in blood glucose, body weight, systolic blood pressure (BP), and urinary volume in control, vehicle-treated diabetic rats, and diabetic rats treated with FTY720 or SEW2871 for 9 weeksControlDiabetes + vehicleDiabetes + FTY720Diabetes + SEW2871Blood glucose (mg/dl) Week 081±478±280±480±5 Week 377±4326±16*P<0.001 compared to control;321±28*P<0.001 compared to control;333±8*P<0.001 compared to control; Week 689±5334±24*P<0.001 compared to control;390±12*P<0.001 compared to control;418±30*P<0.001 compared to control;,†P<0.05 compared to diabetes + vehicle. Week 988±7465±22*P<0.001 compared to control;354±18*P<0.001 compared to control;,†P<0.05 compared to diabetes + vehicle.414±29*P<0.001 compared to control;Body weight (g)514±15264±28*P<0.001 compared to control;285±13*P<0.001 compared to control;268±8*P<0.001 compared to control;Systolic BP (mm Hg)135±3136±2138±3138±2Urinary volume (ml per 24 h)14±141±4*P<0.001 compared to control;33±4*P<0.001 compared to control;39±6*Data are mean±s.e.m.* P<0.001 compared to control;† P<0.05 compared to diabetes + vehicle. Open table in a new tab Data are mean±s.e.m. As expected, diabetic rats treated with vehicle showed a significant progressive increase in UAE that began as early as 3 weeks after STZ, continued at week 6, and peaked at week 9. Both FTY720 and SEW2871 significantly reduced UAE at week 6 and at week 9, compared with vehicle (Figure 1). Masson's trichrome stain of rat kidneys from control rats (Figure 2a and e), diabetic rats treated with vehicle (Figure 2b and f), and diabetic rats treated with FTY720 (Figure 2c and g) or SEW2871 (Figure 2d and h) at week 9 of the study was used to evaluate renal histology. Diabetic rats treated with vehicle (Figure 2b and f) had severe tubular injury associated with vacuolization (tubular injury score, 3.4±0.4; P<0.0001, n=5) compared with control (score, 0.2±0.1, n=7), with slight interstitial fibrosis. Both FTY720 and SEW2871 significantly reduced these histological effects (score 2.3±0.5, n=6 and 2.2±0.3, n=9, respectively; P<0.05 compared with vehicle). Inflammatory cytokines have an important role in DN. Therefore, we assessed the anti-inflammatory effect of FTY720 and SEW2871 treatment on urinary TNF-α level in diabetic rats. Urinary TNF-α excretion increased significantly in the vehicle-treated diabetic rats at week 9, and this increase was reduced by treatment with either FTY720 or SEW2871 administration (Figure 3). As S1P1R activation has been shown previously to reduce peripheral blood and tissue lymphocyte count,11.Mandala S. Hajdu R. Bergstrom J. et al.Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.Science. 2002; 296: 346-349Crossref PubMed Scopus (1367) Google Scholar, 12.Pinschewer D.D. Ochsenbein A.F. Odermatt B. et al.FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.J Immunol. 2000; 164: 5761-5770Crossref PubMed Scopus (324) Google Scholar, 24.Chiba K. Yanagawa Y. Masubuchi Y. et al.FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing.J Immunol. 1998; 160: 5037-5044PubMed Google Scholar we investigated whether the protective effect of FTY720 and SEW2871 in diabetes is mediated by lymphopenia. As shown in Table 2, fluorescence-activated cell sorting analysis revealed no significant effects of FTY720 or SEW2871 treatment compared with vehicle on the kidney content of T cells, B cells, or macrophages in diabetic rats. In contrast, FTY720 but not SEW2871 treatment significantly reduced blood lymphocyte count in diabetic rats (Table 2).Table 2Effects of FTY720 and SEW2871 on blood lymphocyte count and kidney tissue content of T cells, B cells, and macrophages in diabetesMethodDiabetes + vehicleDiabetes + FTY720Diabetes + SEW2871CD3FACSaKidney tissue content of T cells (CD3+, CD8+, CD4+), B cells (CD45R+), and macrophages (CD11b+) was determined by FACS (no of cells × 104) after 9 weeks in diabetic rats.1.1±0.30.6±0.32.0±0.3CD8FACS0.5±0.10.3±0.10.7±0.2CD4FACS1.4±0.30.7±0.22.5±0.7CD45RFACS0.6±0.30.2±0.10.3±0.1CD11bFACS0.7±0.10.8±0.042.9±0.5LymphocyteHEMAVETbBlood lymphocyte count (K/μl: 1000/μl) was determined by using HEMAVET.4.3±0.72.5±0.5*P<0.05 compared with vehicle-treated diabetic rats.4.5±0.7Abbreviations: HEMAVET, veterinary hematology system; FACS, flow cytometry analysis.* P<0.05 compared with vehicle-treated diabetic rats.a Kidney tissue content of T cells (CD3+, CD8+, CD4+), B cells (CD45R+), and macrophages (CD11b+) was determined by FACS (no of cells × 104) after 9 weeks in diabetic rats.b Blood lymphocyte count (K/μl: 1000/μl) was determined by using HEMAVET. Open table in a new tab Abbreviations: HEMAVET, veterinary hematology system; FACS, flow cytometry analysis. We further questioned whether the effect of S1P1R agonist was mediated, at least in part, by inducing lymphopenia in the STZ-induced diabetic model. Therefore, we used Rag-1 mice (which lack T- and B cells) and wild-type (WT) mice. As shown in Figure 4, UAE was increased significantly by STZ-induced diabetes in WT and Rag-1 mice. SEW2871 treatment significantly reduced UAE in diabetic WT group and was associated with reduced lymphocyte count (0.36±0.1K/μl; P<0.01) from vehicle-treated diabetes group (1.27±0.2 K/μl). SEW2871 still reduced UAE in diabetic Rag-1 mice. FTY720 is a non-selective S1P1R agonist, and it may activate other S1P receptors such as S1P3R, S1P4R, and S1P5R. We have shown previously that, of the five subtypes, S1P1R and S1P3R have the highest expression in the kidney.9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar To examine the relative contribution of these two receptor subtypes to FTY720 effect in DN, we induced diabetes in mice deficient in S1P3Rs (S1P3−/−) and their corresponding WT littermate S1P3+/+ controls. FTY720 significantly reduced UAE in STZ-treated S1P3−/− mice (Figure 5). To determine the possible mechanisms by which FTY720 and SEW2871 reduce UAE and mediate renal tissue protection, we examined their effects on podocytes. At 9 weeks of diabetes, both nephrin and podocin (podocyte-specific proteins) mRNA were significantly reduced and were associated with reduced number of WT-1-positive staining (16.2±1.2 cells; P<0.0001) in kidneys from vehicle-treated diabetic rats compared with control (WT-1-positive staining: 30±1 cells). FTY720 and SEW2871 restored and markedly increased the expression of nephrin and podocin in diabetic rats and increased the number of WT-1-positive staining (28±1 cells, P<0.0001; 22±2 cells, P<0.05), respectively, compared with vehicle (Figure 6). These data suggest that FTY720 and SEW2871 could have direct effects on podocytes. To explore this option, first, we examined the expression of S1P receptors and S1P synthetic enzymes in podocytes. We have shown previously that S1P1-4Rs but not S1P5Rs are expressed in kidney, with S1P1Rs having the highest receptor expression.9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar We also showed that both SphK1 and SphK2 are expressed in the kidney.25.Jo S.K. Bajwa A. Ye H. et al.Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury.Kidney Int. 2009; 75: 167-175Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar We now extend these findings and show mRNA expression of S1P1–4Rs, but not of S1P5R (Figure 7a), and of SphK1 and SphK2 (Figure 7b) in an immortalized mouse podocyte cell line, indicating a possible role of endogenous S1P in podocytes under physiological or pathophysiological conditions. To explore this possibility, we cultured immortalized podocytes with normal glucose or high glucose (HG) media for 14 days. Our data show enhanced TNF-α and VEGF mRNA expression after HG media, an effect significantly reduced using SEW2871 treatment (Figure 7c and d). In contrast, there were no effects on podocyte apoptosis (data not shown) in all groups.Figure 7Role of sphingosine 1-phosphate 1 receptor (S1P1R) agonists in immortalized podocytes in vitro. (a, b) Total RNA from immortalized podocytes was extracted and subjected to analysis by reverse transcriptase-PCR (RT-PCR) for S1P receptor mRNA expression (a) and sphingosine kinase 1 and 2 (SphK1 and SphK2) mRNA expression (b). (c, d) Total RNA from immortalized podocytes subjected to normal glucose (NG) or high glucose (HG) media for 14 days with or without SEW2871 (n=5–6 each group) was extracted and subjected to analysis by RT-PCR for tumor necrosis factor-α (TNF-α) mRNA expression (c) and vascular endothelial growth factor (VEGF) mRNA expression (d). Expression of TNF-α and VEGF mRNA was normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Open bars, NG; black bars, HG treated with vehicle; and gray bars, HG treated with SEW2871 (1 μmol/l). Data are means±s.e.m. *P<0.05, **P<0.01 compared with NG; +P<0.05 compared with HG + vehicle.View Large Image Figure ViewerDownload (PPT) This study demonstrates a finding previously unrecognized that FTY720 and SEW2871 have protective effects on renal function and histology in an STZ-induced diabetic rat model. The effect of S1P1R activation in diabetes is probably not due to lymphocyte depletion, as SEW2871 continues to induce renal tissue protection in Rag-1 mice that lack both T and B cells. Furthermore, FTY720 effects are mediated mainly through S1P1R activation, as FTY720 was protective in S1P3−/− mice. FTY720 or SEW2871, either directly by maintaining podocyte-specific proteins and expression of TNF-α and VEGF or indirectly, control glomerular permeability and podocyte function. Additionally, we observed marked reduction of tubule injury and vacuolization, suggesting effects of these compounds on proximal tubule cells. Because progressive kidney disease due to DN results from abnormalities of the glomerulus and the tubulointerstitium, the broad ranging effects of S1P1R agonists might be more effective than current therapies for DN. The biological functions of S1P have been explored in diverse cell types and tissues. However, the exact role of S1P in kidney physiology and pathophysiology remains unclear. S1P regulates a wide variety of important cellular functions.7.Hla T. Lee M.J. Ancellin N. et al.Lysophospholipids—receptor revelations.Science. 2001; 294: 1875-1878Crossref PubMed Scopus (465) Google Scholar, 8.Rosen H. Goetzl E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.Nat Rev Immunol. 2005; 5: 560-570Crossref PubMed Scopus (595) Google Scholar S1P1Rs are expressed in the kidney,9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar, 26.Kluk M.J. Hla T. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors.Biochim Biophys Acta. 2002; 1582: 72-80Crossref PubMed Scopus (265) Google Scholar and have an important role in maintaining endothelial cell integrity27.Lee M.J. Thangada S. Claffey K.P. et al.Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate.Cell. 1999; 99: 301-312Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar, 28.Krump-Konvalinkova V. Yasuda S. Rubic T. et al.Stable knock-down of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells.Arterioscler Thromb Vasc Biol. 2005; 25: 546-552Crossref PubMed Scopus (70) Google Scholar and in trafficking of lymphocytes.29.Goetzl E.J. Rosen H. Regulation of immunity by lysosphingolipids and their G protein-coupled receptors.J Clin Invest. 2004; 114: 1531-1537Crossref PubMed Scopus (103) Google Scholar Recently, we demonstrated that both FTY720 and SEW2871 prevent renal ischemia–reperfusion injury by activating S1P1Rs.9.Awad A.S. Ye H. Huang L. et al.Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney.Am J Physiol Renal Physiol. 2006; 290: F1516-F1524Crossref PubMed Scopus (184) Google Scholar,23.Bajwa A. Jo S.K. Ye H. et al.Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury.J Am Soc Nephrol. 2010; 21: 955-965Crossref PubMed Scopus (84) Google Scholar Our current study extends the role of S1P1Rs from an acute to a chronic model of DN. In this study, we demonstrated a significant increase in UAE after 3 weeks of diabetes in conscious rats, which persisted throughout the study period. Administration of FTY720 or SEW2871 significantly reduced albuminuria associated with diabetes. The effect of S1P1R activation was associated with marked reduction of tubular injury and vacuolization in DN. It is now clear that DN is a tubule–glomerular disorder. Whether S1P1R activation has a direct effect on tubular cells in DN is not clear in this study. However, data from our laboratory show that S1P1R activation mediates renal tissue protection through a direct effect on proximal tubule S1P1Rs in renal ischemia–reperfusion injury.23.Bajwa A. Jo S.K. Ye H. et al.Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury.J Am Soc Nephrol. 2010; 21: 955-965Crossref PubMed Scopus (84) Google Scholar It is possible that tubular cell injury associated with DN contributes, in part, to increased UAE in diabetes and that S1P1R activation reduced albuminuria by protecting tubular injury. Additional study is needed to explore the direct effect of S1P1R activation on tubular cells in DN. Furthermore, the reduction of podocyte mRNA expression of VEGF after SEW2871 treatment of immortalized podocytes following HG suggests that the effects of S1P1R agonists on reducing proteinuria early in the course of diabetes may be mediated by a direct effect on podocytes. We have shown previously that levels of urinary TNF-α were correlated with increases in UAE in diabetes.30.Awad A.S. Huang L. Ye H. et al.Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy.Am J Physiol Renal Physiol. 2006; 290: F828-F837Crossref PubMed Scopus (115) Google Scholar TNF-α is produced mainly by monocytes/macrophages, T and B lymphocytes, and glomerular mesangial cells.31.Baud L. Oudinet J.P. Bens M. et al.Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide.Kidney Int. 1989; 35: 1111-1118Abstract Full Text PDF PubMed Scopus (185) Google Scholar, 32.Hruby Z.W. Lowry R.P. Spontaneous release of tumor necrosis factor alpha by isolated renal glomeruli and cultured glomerular mesangial cells.Clin Immunol Immunopathol. 1991; 59: 156-164Crossref PubMed Scopus (19) Google Scholar Both TNF-α and interleukin-1β have been associated with increased vascular endothelial permeability33.Royall J.A. Berkow R.L. Beckman J.S. et al.Tumor necrosis factor and interleukin 1 alpha increase vascular endothelial permeability.Am J Physiol. 1989; 257: L399-L410PubMed Google Scholar and have been detected in isolated glomerular basement membrane in diabetes.34.Nakamura T. Fukui M. Ebihara I. et al.mRNA expression of growth factors in glomeruli from diabetic rats.Diabetes. 1993; 42: 450-456Crossref PubMed Google Scholar It is possible that S1P1R activation by FTY720 or SEW2871 protects kidneys in DN by reducing kidney inflammatory cytokines such as TNF-α. The fact that TNF-α was undetectable in the blood30.Awad A.S. Huang L. Ye H. et al.Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy.Am J Physiol Renal Physiol. 2006; 290: F828-F837Crossref PubMed Scopus (115) Google Scholar indicates that the source of urinary TNF-α was mainly from the kidney. Interestingly, neither FTY720 nor SEW2871 affected the number of kidney macrophages, as shown by fluorescence-activated cell sorting, suggesting that their effects are mainly mediated through kidney-derived cells producing TNF-α. Our data in podocytes support this hypothesis and show that SEW2871 reduced podocyte mRNA expression of TNF-α after HG. Another observation from our study indicates that SEW2871 treatment elicits more ki" @default.
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• W2007991612 title "Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes" @default.
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